TRP Channel Modulators

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TRP Channel Modulators Transient receptor potential (TRP) channels are ion Representative Compounds and Targets: channels located on the plasma membrane of many different cell types. TRP channels play a significant TRPV A7085 Arvanil: TRPV1 activator role in sensory transduction, pain signal relay, A9818 Azalastine: TRPV1 activator temperature, taste, and pressure. C0266 Capsaicin: TRPV activator TRP vanilloid (TRPV) channels are the most well- C0368 Carveol: TRPV3 activator studied of these channels. Capsaicin (C0266) and G3252 6-Gingerol: TRPV1 activator Piperine (P3465) are TRPV channel activators M1979 Methyl Salicylate: TRPV1 activator/blocker found in plant sources and are responsible for the N1755 Neomycin Sulfate: TRPV1 blocker 1 P1634 Peimine: TRPV1 and TRPA1 blocker hot or spicy flavor of some peppers . P1635 Peiminine: TRPV1 and TRPA1 blocker TRP canonical (TRPC) channels are often found P3465 Piperine: TRPV activator on cardiomyocytes and nerves; TRPC channels R1774 Resiniferatoxin: TRPV activator play a role in cardiac hypertrophy2. Amyotrophic S8151 Sumatriptan: TRPV1 blocker lateral sclerosis (ALS) treatment Riluzole (R3347) T6902 Tranilast: TRPV2 blocker activates TRPC5 channels. Clemizole (C4417), TRPC a NS4B and histamine receptor blocker, inhibits C4417 Clemizole: TRPC5 blocker TRPC5 channels, potentially regulating F4483 Flufenamic Acid: TRPC3 and TRPM2 blocker neurite length3. N5311 Nocistatin: TRPC activator TRP melastatin-like (TRPM) channels are involved R3347 Riluzole: TRPC5 activator in temperature and taste transduction as well as TRPM cell adhesion. Icillin (I0933) activates TRPM8 G3456 Ginsenoside Rd: TRPM7 blocker channels and inhibits TRPV3 channels, acting I0933 Icillin: TRPM8 activator, TRPV3 blocker as a cooling agent4. Other TRP channels P7023 Pregnenolone: TRPM3 activator include TRP Ankyrin (TRPA) channels, TRP polycystin (TRPP) channels and TRP mucolipin TRPA A0817 1’-Acetoxychavicol Acetate: TRPA activator (TRPML) channels. E7556 Etodolac: TRPA activator P0270 Parthenolide: TRPA activator References: 1. Kissin I. Anesth Analg. 2008 Jul;107(1):271-81. 2. Bush EW, Hood DB, Papst PJet al. J Biol Chem. 2006 Nov 3;281(44):33487-96. 3. Richter JM, Schaefer M, Hill K. Mol Pharmacol. 2014 Nov;86(5):514- 21. 4. Sherkheli MA, Gisselmann G, Hatt H. ScientificWorldJournal. 2012;2012:982725. Specialty Chemicals for Life Science Research LKT Laboratories, Inc. • lktlabs.com • Phone: 651-644-8424 • Fax: 651-644-8357 .

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Transient Receptor Potential (TRP) Channels in Haematological Malignancies: an Update
biomolecules Review Transient Receptor Potential (TRP) Channels in Haematological Malignancies: An Update Federica Maggi 1,2 , Maria Beatrice Morelli 2 , Massimo Nabissi 2 , Oliviero Marinelli 2 , Laura Zeppa 2, Cristina Aguzzi 2, Giorgio Santoni 2 and Consuelo Amantini 3,* 1 Department of Molecular Medicine, Sapienza University, 00185 Rome, Italy; [email protected] 2 Immunopathology Laboratory, School of Pharmacy, University of Camerino, 62032 Camerino, Italy; [email protected] (M.B.M.); [email protected] (M.N.); [email protected] (O.M.); [email protected] (L.Z.); [email protected] (C.A.); [email protected] (G.S.) 3 Immunopathology Laboratory, School of Biosciences and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy * Correspondence: [email protected]; Tel.: +30-0737403312 Abstract: Transient receptor potential (TRP) channels are improving their importance in differ- ent cancers, becoming suitable as promising candidates for precision medicine. Their important contribution in calcium trafﬁcking inside and outside cells is coming to light from many papers published so far. Encouraging results on the correlation between TRP and overall survival (OS) and progression-free survival (PFS) in cancer patients are available, and there are as many promising data from in vitro studies. For what concerns haematological malignancy, the role of TRPs is still not elucidated, and data regarding TRP channel expression have demonstrated great variability throughout blood cancer so far. Thus, the aim of this review is to highlight the most recent ﬁndings Citation: Maggi, F.; Morelli, M.B.; on TRP channels in leukaemia and lymphoma, demonstrating their important contribution in the Nabissi, M.; Marinelli, O.; Zeppa, L.; perspective of personalised therapies.
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Structure of the Mouse TRPC4 Ion Channel 1 2 Jingjing
bioRxiv preprint doi: https://doi.org/10.1101/282715; this version posted March 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Structure of the mouse TRPC4 ion channel 2 3 Jingjing Duan1,2*, Jian Li1,3*, Bo Zeng4*, Gui-Lan Chen4, Xiaogang Peng5, Yixing Zhang1, 4 Jianbin Wang1, David E. Clapham2, Zongli Li6#, Jin Zhang1# 5 6 7 1School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, 330031, China. 8 2Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA 9 3Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 10 40536, USA. 11 4Key Laboratory of Medical Electrophysiology, Ministry of Education, and Institute of 12 Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China 13 5The Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang 14 University, Nanchang 330006, China. 15 6Howard Hughes Medical Institute, Department of Biological Chemistry and Molecular 16 Pharmacology, Harvard Medical School, Boston, MA 02115, USA. 17 18 *These authors contributed equally to this work. 19 # Corresponding authors bioRxiv preprint doi: https://doi.org/10.1101/282715; this version posted March 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 Abstract 21 Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They 22 mediate functions ranging from neuronally-mediated hot and cold sensation to intracellular 23 organellar and primary ciliary signaling.
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Expression of Transient Receptor Potential Channels in the Ependymal Cells of the Developing Rat Brain
Original Article http://dx.doi.org/10.5115/acb.2013.46.1.68 pISSN 2093-3665 eISSN 2093-3673 Expression of transient receptor potential channels in the ependymal cells of the developing rat brain Kwang Deog Jo1, Kyu-Seok Lee2, Won Taek Lee3, Mi-Sun Hur2, Ho-Jeong Kim2 1Department of Neurology, Gangneung Asan Hospital, University of Ulsan College of Medicine, 2Department of Anatomy, Kwandong University College of Medicine, Gangneung, 3Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea Abstract: Cerebrospinal fluid (CSF) plays an important role in providing brain tissue with a stable internal environment as well as in absorbing mechanical and thermal stresses. From its initial composition, derived from the amniotic fluid trapped by the closure of neuropores, CSF is modified by developing and differentiating ependymal cells lining the ventricular surface or forming the choroid plexus. Its osmolarity and ionic composition brings about a change through the action of many channels expressed on the ependymal cells. Some newly discovered transient receptor potential (TRP) channels are known to be expressed in the choroid plexus ependyma. To detect additional TRP channel expression, immunohistochemical screening was performed at the choroid plexus of 13-, 15-, 17-, and 19-day embryos, using antibodies against TRPV1, TRPV3, and TRPA1, and the expression was compared with those in the adult TRP channels. The level of TRP channel expression was higher in the choroid plexus which suggests more active functioning of TRP channels in the developing choroid plexus than the ventricular lining ependyma in the 15- and 17-day embryos. All the expression of TRP channels decreased at the 19th day of gestation.
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Investigational Drugs in Early Phase Clinical Trials Targeting Thermotransient Receptor Potential (Thermotrp) Channels
Expert Opinion on Investigational Drugs ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieid20 Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels Asia Fernández-Carvajal , Rosario González-Muñiz , Gregorio Fernández- Ballester & Antonio Ferrer-Montiel To cite this article: Asia Fernández-Carvajal , Rosario González-Muñiz , Gregorio Fernández- Ballester & Antonio Ferrer-Montiel (2020): Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2020.1825680 To link to this article: https://doi.org/10.1080/13543784.2020.1825680 Published online: 29 Sep 2020. Submit your article to this journal Article views: 31 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ieid20 EXPERT OPINION ON INVESTIGATIONAL DRUGS https://doi.org/10.1080/13543784.2020.1825680 REVIEW Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels Asia Fernández-Carvajala, Rosario González-Muñizb, Gregorio Fernández-Ballestera and Antonio Ferrer-Montiela aInstituto De Investigación, Desarrollo E Innovación En Biotecnología Sanitaria De Elche (Idibe), Universitas Miguel Hernández, Alicante, Spain; bInstituto De Química Médica, CSIC, Madrid, Spain ABSTRACT ARTICLE HISTORY Introduction: Thermo transient receptor potential (thermoTRP) channels are some of the most inten Received 15 June 2020 sely pursued therapeutic targets of the past decade. They are considered promising targets of numer Accepted 15 September ous diseases including chronic pain and cancer. Modulators of these proteins, in particular TRPV1-4, 2020 TRPM8 and TRPA1, have reached clinical development, but none has been approved for clinical practice KEYWORDS yet.
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New Natural Agonists of the Transient Receptor Potential Ankyrin 1 (TRPA1
www.nature.com/scientificreports OPEN New natural agonists of the transient receptor potential Ankyrin 1 (TRPA1) channel Coline Legrand, Jenny Meylan Merlini, Carole de Senarclens‑Bezençon & Stéphanie Michlig* The transient receptor potential (TRP) channels family are cationic channels involved in various physiological processes as pain, infammation, metabolism, swallowing function, gut motility, thermoregulation or adipogenesis. In the oral cavity, TRP channels are involved in chemesthesis, the sensory chemical transduction of spicy ingredients. Among them, TRPA1 is activated by natural molecules producing pungent, tingling or irritating sensations during their consumption. TRPA1 can be activated by diferent chemicals found in plants or spices such as the electrophiles isothiocyanates, thiosulfnates or unsaturated aldehydes. TRPA1 has been as well associated to various physiological mechanisms like gut motility, infammation or pain. Cinnamaldehyde, its well known potent agonist from cinnamon, is reported to impact metabolism and exert anti-obesity and anti-hyperglycemic efects. Recently, a structurally similar molecule to cinnamaldehyde, cuminaldehyde was shown to possess anti-obesity and anti-hyperglycemic efect as well. We hypothesized that both cinnamaldehyde and cuminaldehyde might exert this metabolic efects through TRPA1 activation and evaluated the impact of cuminaldehyde on TRPA1. The results presented here show that cuminaldehyde activates TRPA1 as well. Additionally, a new natural agonist of TRPA1, tiglic aldehyde, was identifed
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Snapshot: Mammalian TRP Channels David E
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Ca Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart
Journal of Cardiovascular Development and Disease Review Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases Jianlin Feng 1, Maria K. Armillei 1, Albert S. Yu 1, Bruce T. Liang 1, Loren W. Runnels 2,* and Lixia Yue 1,* 1 Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA; [email protected] (J.F.); [email protected] (M.K.A.); [email protected] (A.S.Y.); [email protected] (B.T.L.) 2 Department of Pharmacology, Rutgers, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA * Correspondence: [email protected] (L.W.R.); [email protected] (L.Y.) Received: 11 August 2019; Accepted: 18 September 2019; Published: 23 September 2019 Abstract: Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca2+ signaling plays a vital role in this pathological process, what contributes to Ca2+ signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca2+ signaling. Intracellular Ca2+ signals are generated by Ca2+ release from intracellular Ca2+ stores and by Ca2+ entry through a multitude of Ca2+-permeable ion channels in the plasma membrane.
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Ion Channels 3 1
r r r Cell Signalling Biology Michael J. Berridge Module 3 Ion Channels 3 1 Module 3 Ion Channels Synopsis Ion channels have two main signalling functions: either they can generate second messengers or they can function as effectors by responding to such messengers. Their role in signal generation is mainly centred on the Ca2 + signalling pathway, which has a large number of Ca2+ entry channels and internal Ca2+ release channels, both of which contribute to the generation of Ca2 + signals. Ion channels are also important effectors in that they mediate the action of different intracellular signalling pathways. There are a large number of K+ channels and many of these function in different + aspects of cell signalling. The voltage-dependent K (KV) channels regulate membrane potential and + excitability. The inward rectifier K (Kir) channel family has a number of important groups of channels + + such as the G protein-gated inward rectifier K (GIRK) channels and the ATP-sensitive K (KATP) + + channels. The two-pore domain K (K2P) channels are responsible for the large background K current. Some of the actions of Ca2 + are carried out by Ca2+-sensitive K+ channels and Ca2+-sensitive Cl − channels. The latter are members of a large group of chloride channels and transporters with multiple functions. There is a large family of ATP-binding cassette (ABC) transporters some of which have a signalling role in that they extrude signalling components from the cell. One of the ABC transporters is the cystic − − fibrosis transmembrane conductance regulator (CFTR) that conducts anions (Cl and HCO3 )and contributes to the osmotic gradient for the parallel flow of water in various transporting epithelia.
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STRUCTURAL AND FUNCTIONAL STUDIES OF TRPML1 AND TRPP2 Nicole Marie Benvin Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2017 © 2017 Nicole Marie Benvin All Rights Reserved ABSTRACT Structural and Functional Studies of TRPML1 and TRPP2 Nicole Marie Benvin In recent years, the determination of several high-resolution structures of transient receptor potential (TRP) channels has led to significant progress within this field. The primary focus of this dissertation is to elucidate the structural characterization of TRPML1 and TRPP2. Mutations in TRPML1 cause mucolipidosis type IV (MLIV), a rare neurodegenerative lysosomal storage disorder. We determined the first high-resolution crystal structures of the human TRPML1 I-II linker domain using X-ray crystallography at pH 4.5, pH 6.0, and pH 7.5. These structures revealed a tetramer with a highly electronegative central pore which plays a role in the dual Ca2+/pH regulation of TRPML1. Notably, these physiologically relevant structures of the I-II linker domain harbor three MLIV-causing mutations. Our findings suggest that these pathogenic mutations destabilize not only the tetrameric structure of the I-II linker, but also the overall architecture of full-length TRPML1. In addition, TRPML1 proteins containing MLIV- causing mutations mislocalized in the cell when imaged by confocal fluorescence microscopy. Mutations in TRPP2 cause autosomal dominant polycystic kidney disease (ADPKD). Since novel technological advances in single-particle cryo-electron microscopy have now enabled the determination of high-resolution membrane protein structures, we set out to solve the structure of TRPP2 using this technique.
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Conserved Allosteric Pathways for Activation of TRPV3 Revealed Through Engineering Vanilloid-Sensitivity Feng Zhang1,2*, Kenton Jon Swartz1, Andres Jara-Oseguera1*
RESEARCH ARTICLE Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity Feng Zhang1,2*, Kenton Jon Swartz1, Andres Jara-Oseguera1* 1Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States; 2Department of Biochemistry, University of Utah, Salt Lake City, United States Abstract The Transient Receptor Potential Vanilloid 1 (TRPV) channel is activated by an array of stimuli, including heat and vanilloid compounds. The TRPV1 homologues TRPV2 and TRPV3 are also activated by heat, but sensitivity to vanilloids and many other agonists is not conserved among TRPV subfamily members. It was recently discovered that four mutations in TRPV2 are sufficient to render the channel sensitive to the TRPV1-specific vanilloid agonist resiniferatoxin (RTx). Here, we show that mutation of six residues in TRPV3 corresponding to the vanilloid site in TRPV1 is sufficient to engineer RTx binding. However, robust activation of TRPV3 by RTx requires facilitation of channel opening by introducing mutations in the pore, temperatures > 30˚C, or sensitization with another agonist. Our results demonstrate that the energetics of channel activation can determine the apparent sensitivity to a stimulus and suggest that allosteric pathways for activation are conserved in the TRPV family. DOI: https://doi.org/10.7554/eLife.42756.001 *For correspondence: [email protected] (FZ); Introduction [email protected] (AJ) Transient receptor potential (TRP) cation channels are involved in a diverse array of physiological functions (Li, 2017), with many of them acting as sensory detectors of stimuli such as temperature, Competing interest: See natural products and various cell-signaling molecules (Flockerzi, 2007).
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The Ca2+-Permeable Cation Transient Receptor Potential
1521-0111/92/3/193–200$25.00 https://doi.org/10.1124/mol.116.107946 MOLECULAR PHARMACOLOGY Mol Pharmacol 92:193–200, September 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW—MOLECULAR PHARMACOLOGY IN CHINA The Ca21-Permeable Cation Transient Receptor Potential TRPV3 Channel: An Emerging Pivotal Target for Itch and Skin Diseases Gongxin Wang and KeWei Wang Department of Pharmacology, Qingdao University School of Pharmacy and Institute of Innovative Drugs, Qingdao University, Downloaded from Qingdao, Shandong Province, China Received December 20, 2016; accepted March 31, 2017 ABSTRACT Temperature-sensitive transient receptor potential (TRP) chan- syndrome, which is characterized by severe itching and molpharm.aspetjournals.org nels such as TRPA1 and TRPV1 have been identified as down- palmoplantar and periorificial keratoderma, unveils its crucial stream ion channel targets in the transduction of itch. As a member role in chronic itch and skin diseases. In this review, we will of the temperature-sensitive TRP family, the Ca21-permeable focus on recent progress made in the understanding of nonselective cation channel TRPV3 is expressed abundantly TRPV3 that emerges as an attractive target for developing in skin keratinocytes. Recent identification of gain-of-function effective antipruritic therapy for chronic itch or skin-related mutations of human TRPV3 from patients with Olmsted diseases. attractive target for developing antipruritic therapy in chronic Introduction at ASPET Journals on September 28, 2021 itch or skin-related diseases. Itch (also known as pruritus) is an unpleasant sensation of The superfamily of TRP channels is composed of 28 mam- the skin, provoking the desire or reflex to scratch.
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Cytoplasmic Inter-Subunit Interface Controls Use-Dependence of Thermal Activation of TRPV3 Channel
International Journal of Molecular Sciences Article Cytoplasmic Inter-Subunit Interface Controls Use-Dependence of Thermal Activation of TRPV3 Channel Lucie Macikova 1,2 , Lenka Vyklicka 1, Ivan Barvik 3, Alexander I. Sobolevsky 4 and Viktorie Vlachova 1,* 1 Department of Cellular Neurophysiology, Institute of Physiology Czech Academy of Sciences, 142 20 Prague, Czech Republic 2 Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic 3 Division of Biomolecular Physics, Institute of Physics, Faculty of Mathematics and Physics, Charles University, 121 16 Prague, Czech Republic 4 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA * Correspondence: [email protected]; Tel.: +420-296-442-711 Received: 23 July 2019; Accepted: 13 August 2019; Published: 16 August 2019 Abstract: The vanilloid transient receptor potential channel TRPV3 is a putative molecular thermosensor widely considered to be involved in cutaneous sensation, skin homeostasis, nociception, and pruritus. Repeated stimulation of TRPV3 by high temperatures above 50 ◦C progressively increases its responses and shifts the activation threshold to physiological temperatures. This use-dependence does not occur in the related heat-sensitive TRPV1 channel in which responses decrease, and the activation threshold is retained above 40 ◦C during activations. By combining structure-based mutagenesis, electrophysiology, and molecular modeling, we showed that chimeric replacement of the residues from the TRPV3 cytoplasmic inter-subunit interface (N251–E257) with the homologous residues of TRPV1 resulted in channels that, similarly to TRPV1, exhibited a lowered thermal threshold, were sensitized, and failed to close completely after intense stimulation. Crosslinking of this interface by the engineered disulﬁde bridge between substituted cysteines F259C and V385C (or, to a lesser extent, Y382C) locked the channel in an open state.
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